Chronic inflammation is causally associated with the development of many cancers, often resulting in a cytokine storm that facilitates tumor progression. Therapy could be directed to appropriately quiet the storm while beneficial for the tumor, could result in negative effects on the host. The NF-?B family of transcription factors is required for the generation of the 'cytokine storm'. Malignant melanoma, the most deadly type of skin cancer, provides a uniquely valuable model for testing the balance between immunity and intrinsic resistance in tumor growth. We have demonstrated that inhibiting IKK2, the major kinase that activates the canonical NF-?B pathway, in melanoma tumor bearing mice results in reduced tumor growth. Moreover, targeted deletion of IKK2 in melanocytes prevents mutant Ras-mediated melanoma tumor formation in mice that have lost the tumor suppressors INK4a/ARF. Current therapies for disseminated melanoma are largely ineffective. Small molecule inhibitors of IKK2, by directly blocking the canonical NF-?B pathway, may be effective in the clinic for metastatic melanoma. Aurora Kinase (Aurk) inhibitors readily block cell cycle progression in tumor cells and also indirectly inhibit NF-kB, while inhibitors of NF-?B inhibit Aurk and target many types of tumor cells for apoptosis. Clinical trials are currently ongoing using small molecule inhibitors of IKK2 and AurK for other solid tumors and haematological malignancies. Melanoma might be highly responsive to inhibitors to these two kinases, but before initiating such studies, potentially harmful effects of inhibiting the NF-kB pathway on the host immune response require clarification. In this proposal we will test the hypothesis that the benefits of targeting IKK2 or AurkA will outweigh the risks for patients with aggressive metastatic melanoma and constitutive activation of these pathways. We also hypothesize that inhibiting NF-kB with IKK2 or AurKA inhibitors will boost the immune response to the tumor by shifting leukocyte profile in the tumor microenvironment from one that is pro-tumorigenic (M2, N2, Th2) to one that is anti-tumorigenic (M1/N1/Th1). Moreover, there are documented cases of tumors developing resistance to Aurk inhibitors and in these instances we hypothesize that resistance to therapy with Aurk or IKK inhibitors will be associated with mutations in Aurk or kinases in the IKK pathway. There are three specific aims: 1) To determine whether treatment with IKK2 or AurkA inhibitors results in loss of intrinsic immunity to silent tumors. 2) To characterize the effects of systemic inhibition of IKK2 versus AurkA on the leukocytes infiltrate and cytokine profile in the tumor microenvironment; 3) To characterize the mechanism by which melanoma tumors sensitive to IKK2 or Aurk inhibitors become growth arrested then later resistant to these inhibitors. Insights from this pre-clinical work should allow appropriate design of clinical trials to test the efficacy of IKK2 and Aurk inhibitors for melanoma therapy. The ultimate goal of this work is to develop insight for improved individualized therapy for malignant melanoma patients to increase survival.